Project Summary We are interested in the dynamic interplay between the intracellular distribution of mitochondria and cellular function. Mitochondria are important not only for cellular energy production but also play critical roles in cell cycle progression, differentiation, immune responses, lipid and calcium homeostasis, and apoptotic cell death. These diverse roles are intimately connected to mitochondrial shape and cellular position. Thus, it is not surprising aberrant mitochondrial architecture has been implicated in an ever-increasing number of diseases. Mitochondrial shape and position depend on the integrated and regulated activities of mitochondrial dynamics, motility, and tethering. A key question is how these activities are coordinated to drive the context-specific changes in the shape and position of mitochondria required to meet cellular needs. To begin to address this question, an understanding of the molecular basis of these mitochondrial activities is essential. While mitochondrial tethering plays a critical role in mitochondrial position and function in cells from yeast to neurons, it is the least understood of the activities that shape and position mitochondria. In the aims of this grant, we will address this deficit by exploiting the strengths of the facile yeast system and our expertise in cell biological and biochemical approaches to elucidate the molecular basis, mechanism, and regulation of two tether complexes that function in the distribution and inheritance of mitochondria. Understanding fundamental mechanisms used by cells to position mitochondria will provide insight into how regulated mitochondrial tethering can be harnessed to influence mitochondrial function and overall cellular homeostasis and fitness.